Nasal congestion, obstruction relief, and drug delivery

ABSTRACT

A nasal insert may include a wall in the shape of a tube, the wall including a first end defining a first orifice and a second end defining a second orifice. The first end may have a diameter, diagonal measurement, or cross-sectional area larger than that of the second end. The first end may define at least one break in the wall, so that the first end incompletely encircles the first orifice. The second end may completely encircle the second orifice.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 13/848,374, filed Mar.21, 2013, which is a continuation of Ser. No. 11/290,047, filed Nov. 30,2005, now U.S. Pat. No. 8,403,954, which is a continuation-in-part ofU.S. patent application Ser. No. 10/842,220, filed May 10, 2004, nowU.S. Pat. No. 9,474,642, which is a continuation-in-part of U.S. patentapplication Ser. No. 10/434,669, filed May 9, 2003, now U.S. Pat. No.7,390,331, which is a continuation-in-part of U.S. patent applicationSer. No. 09/862,966, filed May 22, 2001, now U.S. Pat. No. 6,562,057,the disclosures of each of which are hereby incorporated herein byreference.

FIELD

This disclosure pertains to methods and devices for nasal congestion,obstruction relief; and nasal drug delivery, and in particular tomethods and devices for improving nasal breathing, treatment of sinusconditions, and reducing snoring.

BACKGROUND

Nasal obstruction is characterized by anatomical conditions includingnasal valve collapse, nasal valve obstruction, septal deviation, andmedium hypertrophy. These conditions obstruct and restrict nasal airflowcausing difficulties in breathing through the nose.

Limited or obstructed nasal airflow reduces the normal ventilation ofsinuses. Properly ventilated sinuses allow healthy draining for cleaningof the sinuses. Without proper ventilation, sinuses may not drainproperly, which can cause infections in the sinuses. Chronic sinusitisis a condition characterized by long lasting sinus infections, which arecaused by obstructed or restricted nasal airflow.

Snoring is a condition characterized by rough, loud, rattling breathing,or aspiratory noise in the throat during sleep or deep coma. Thecharacteristic snoring noise is produced by vibration of the soft palate(the soft tissue in the roof of the mouth near the throat) or vocalchords by inhaled or exhaled air. As the soft palate vibrates, the lips,cheeks, and nostrils may also vibrate, making the snoring louder.

Snoring can be caused by underlying physical or disease conditions thatrestrict air passages and force the patient to breathe through theirmouth with exaggerated force to move air through narrowed nasalpassages. Chronic snoring can be the result of obstruction of nasalairways, septal deviation, or obstructed nasal passages. Temporarysnoring, or a sudden onset of snoring can be the result of congestion orswollen nasal mucus membranes, as with a cold or hay fever, or a nasalpolyp.

Anatomical deformities in the airway such as septal deviation, mediumhypertrophy, obstructed nasal valves and nasal valve collapse candiminish the airway size. Fat deposits around the nasal passages, asfound in obesity, can make the nasal passages smaller. Poor muscle tonein the muscles of the tongue and throat, or medications and foods (suchas alcohol) that relax these muscles also increase snoring.

Snoring can cause relationship problems between partners, and lead to aloss of intimacy and deterioration of relationships. Loss of sleep, orinsufficient rest during sleep increases irritability, reduces memoryand concentration, and decreases work performance.

A number of methods and devices have been developed to reduce oreliminate snoring. Some devices are external to the patient and includebuzzer systems and alarms that wake the patient. Special pillows, neckcollars, chin braces and head straps have also been tested in an effortto control snoring. When nasal obstruction, chronic sinusitis, orsnoring is caused by serious deformity, surgery has been performed toremove anatomical obstructions, such as removing tonsils, or correctingmedium hypertrophy, or septal deviation. For snoring, occasionally aprocedure called UPPP (Uvulopalatopharyngoplasty) is recommended. Thisprocedure acts like an internal facelift, tightening loose tissue.However, the success rate is only 50%. Laser surgery to correct airwaydefects is also available in some cases.

Other remedies for chronic sinusitis or snoring include prescriptionantibiotics, herbal and homeopathic rinses, sprays or portions, and OTCmedications such as decongestants and anti-histamines. Diet andlifestyle changes may reduce snoring to some degree. Nasal valvecollapse is a soft tissue condition that is inoperable. Remedies arelimited to rigid and metal spring like products. Use of these type ofproducts is limited due to the discomfort or metal taste.

Various devices have been developed for nasal congestion and obstructionrelief and sinus or snore relief that keep the mouth, or nasal passagesopen, or the tongue depressed. Devices marketed for snoring through thedental channel can be expensive custom-fit, or inexpensive over thecounter mouth pieces. Adhesive nasal strips, which are appliedexternally to either side of the nose, have been developed. While thesestrips may dilate the nasal passages to small degree, they do not workwell in patients with significant anatomical deformities or obstructionsin the nose. Air masks that force pressurized air into the mouth andlungs are available. These devices can be cumbersome, unsightly,painful, or expensive, and the patient may abandon these approaches inshort time.

Sinusitis is another common nasal disease. Sinusitis is inflammation orinfection of the mucous membranes that line the inside of the nose andsinuses. It can be caused by bacteria, viruses, and possibly byallergies. Chronic sinusitis is a prolonged sinus infection whichgenerally last longer than 12 weeks. Chronic sinusitis is difficult totreat because it responds slowly to medications. Conventional treatmentfor chronic sinusitis includes oral antibiotics, nasal spray, and sinussurgery. These treatments generally cannot get directly to the source ofthe problem, or they may cause undesirable side effects.

SUMMARY

The disclosed devices and methods may be used to increase airflowthrough the nasal passages. Such increase can help reduce or eliminate awide variety of nasal, sinus, and upper airway disorders, includingsnoring, sleep apnea, nasal congestion, and nasal obstruction. Thedisclosed devices and methods may also be used to treat chronicsinusitis, rhinitis, and allergies.

In one embodiment, a nasal insert may include a wall in the shape of atube, the wall including a first end defining a first orifice and asecond end defining a second orifice. The first end may have a diameter,diagonal measurement, or cross-sectional area larger than that of thesecond end. The first end may define at least one break in the wall, sothat the first end incompletely encircles the first orifice. The secondend may completely encircle the second orifice.

In another embodiment, a nasal insert may include a wall in the shape ofa tube, the wall including a first end defining a first orifice and asecond end defining a second orifice. The first end may have a diameter,diagonal measurement, or cross-sectional area larger than that of thesecond end. The first end may include at least one thinned or webbedportion that is more flexible that the rest of the first end. The secondend may completely encircle the second orifice.

In another embodiment, a “dual tube” nasal breathing assist devices mayhave a pair of open-ended tubular elements connected together by acoupler element. The tubular elements are preferably conic-frustumshaped along a tube axis, having a relatively large first end and arelatively smaller second end, and tapering from the first end to thesecond end along the tube axis. In some embodiments, each tubularelement may have passageways extending through the tubular elementstransverse to the tube axis. These passageways may be elongated, andextend at least in part in the direction of the tube axes.

The coupler element maintains the tubular elements in a generallyparallel relationship to each other in a common plane and in aspaced-apart relation which corresponds generally to the separationbetween the user's nostrils.

In one embodiment, the coupler element is a resilient, nominally curvedstrut lying in a plane substantially perpendicular to the tube axes,permitting relative angular motion of the tube elements about an axisperpendicular to the tube axes.

In an alternate embodiment, the coupler element is a resilient,nominally curved strut lying in a plane substantially parallel to thetube axes, permitting relative angular motion of the tube element aboutan axis parallel to the tube axes.

In another embodiment of the invention, a “single tube” nasal breathingassist device is a single, open-ended, resilient tubular element,adapted for insertion into a user's nostril. The tubular element isconic-frustum shaped, having a relatively large diameter first end and arelatively smaller diameter second end, and a taper extending from thefirst end to the second end along a tube axis. The tubular element mayhave passageways extending through the tubular element transverse to thetube axis. In one form, these passageways may be elongated. The singletube may be used in a user's nostril, and if desired, together withanother single tube in the user's other nostril. In this form, the tubesare not coupled to each other.

In some forms of both the single tube or dual tube embodiments of theinvention, the tubular elements have a tab extending from the first(i.e. relatively large) end which extends substantially parallel to thetube axis and is elongated in the direction of the tube axis. In yetanother embodiment, each tube element has a tab support extendingradially from the first end in a direction substantially perpendicularto the tube axis. At least one tab extends from the tab support, and iselongated in the direction of the tube axis. The tabs may be resilientlydeformable, so as to permit elastic deformation in use, providing africtional holding force when engaging the nose. Alternatively, the tabsmay be non-resiliently deformable, permitting inelastic deformation, sothat a user can “pinch” the tabs so that they capture and hold the nose.The non-resilient tabs are preferably made with a stiffening materialembedded in, affixed to, or of plastic or metal, for example, copper,aluminum, but may be made of other materials that may be non-resilientlydeformed. The tab preferably includes at least one relatively smallprotrusion extending from a distal end of the tab. The distal end isdistal from the first end of the tubular element. The relatively smallprotrusion may also extend from the outer surface of the tubular elementopposing the distal end of the tab. The tab and the protrusion help toprevent the device from slipping out of a user's nose.

In another embodiment, the tab has an inner surface, which faces thetubular element and is at least partially coated with adhesive. In use,after the device is inserted into a user's nostrils, the tab and theouter surface of the tubular element hold the lateral wall of the user'snose, and the adhesive coating increases the friction between the taband the outer surface of the user's nose, and make the tab stick to theouter surface of the user's nose, thus increasing the stability of thedevice within the user's nose.

The tubular element includes, preferably at its large end, an open-facedchannel extending about its tube axis. The device further includes afilter having a peripheral frame contoured to snap-fit in the open-facedchannel. The filter includes a filter medium, preferably but notnecessarily, a composite filter of manmade or natural materials, i.e.paper, metal or plastic with or without a coating of absorbentmaterials, spanning the peripheral frame. In an alternate embodiment, atleast one relative small protrusion extends from an inner surface of thechannel. The filter is adapted to snap-fit over the protrusion into thechannel and is retained by the protrusion, so that the filter cannotslip out from the channel when the device is in use. In a preferredembodiment, the protrusion extends throughout an inner circumference ofthe channel. In another preferred form, the filter includes a linerportion extending along a central axis between a relatively large endand a relatively small end, and a filter medium spanning at least one ofthe relatively large end and the relatively small end. In an alternativeform, the liner portion and the filter medium are integrally constructedfrom a sheet or composite of a filter medium.

In another embodiment, the device is embedded or coated with atherapeutic agent or further includes at least one carrier, which may ormay not be removable, which may include a medium, for example a metal orplastic mesh, or a surface, adapted to bear a therapeutic agent. Thecarrier may be a disc, tablet, or a liner that affixes to the inside ofthe tubular element. The these embodiments may include two oppositeedges, and can include multi-edged configurations, for example as in astar shape. The tubular element further defines two or more opposingchannels on an inner surface of the tubular element. The two or moreopposing channels extend in a plane substantially parallel to thecentral axis and are adapted to receive the two or more opposite edgesof said removable or permanently placed carrier. The therapeutic agentmay be medications, for example, antibiotics, for treating chronicsinusitis or other nasal diseases.

In a further embodiment, the tubular element includes at least onesubstantially annular-shaped stiffening element affixed to the one ortwo ends of the tubular element, or to the middle portion of the tubularelement. The tubular element may also include stiffening element withother configurations affixed to side wall of the tubular element. Thevarying shaped stiffening element is preferably embedded in the tubularelement, but also can be attached to the inner or outer surface of thetubular element.

In a further preferred embodiment, the tubular element is made from ashape memory material.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects of this invention, the various featuresthereof, as well as the invention itself, may be more fully understoodfrom the following description, when read together with the accompanyingdrawings, in which:

FIG. 1 is a perspective view of one embodiment of the present invention;

FIG. 2 shows a side view of the embodiment shown in FIG. 1;

FIG. 3A shows a side view of an alternate embodiment of the invention;

FIG. 3B shows a side view of the embodiment of FIG. 3A rotated about anaxis;

FIG. 4A is a perspective view of an alternate embodiment of theinvention;

FIG. 4B is a perspective view of another alternate embodiment of theinvention;

FIG. 5A is a perspective view of an alternate embodiment of theinvention;

FIG. 5B is a perspective view of yet another embodiment of theinvention;

FIG. 5C is a perspective view of another embodiment of the invention;

FIG. 5D is a perspective view of another embodiment of the invention;

FIG. 5E is a perspective view of another embodiment of the invention;

FIG. 6 shows a schematic view of a filter in accordance with oneembodiment of the present invention;

FIG. 7 shows a cross-sectional view of an alternate embodiment of theinvention;

FIG. 8 shows the filter of FIG. 6 together with the nasal breathingassist device;

FIG. 9 shows another preferred embodiment of the invention;

FIG. 10A shows a schematic view of a filter in accordance with onepreferred embodiment of the present invention;

FIG. 10B shows a schematic view of a filter in accordance with anotherpreferred embodiment of the present invention;

FIG. 11A shows a perspective view of another preferred embodiment of thepresent invention;

FIG. 11B shows a perspective view of another preferred embodiment of thepresent invention; and

FIG. 12 is a representation of one embodiment of the invention in use.

FIGS. 13-21 depict additional devices embodying various disclosedfeatures.

DETAILED DESCRIPTION

The nasal breathing assist devices according to the various aspects ofthe invention are shown in FIGS. 1 through 10. These devices overcomethe deficiencies in the currently available devices. The illustrateddevices are small, inconspicuous in use, and require no specialattachments or fittings, although they may be combined with otherdevices, such as cannulas. The devices are worn inside the nose, so thatthe nasal passages are kept open from the inside, rather than byexternal means. This allows the devices to maintain airways in noseswhere nasal obstructions, inflammatory or structural anatomicaldeviations diminish the effectiveness of externally applied strips. Thedevices can be used alone, or in conjunction with decongestant andantihistamines powders, tablets or liquid medications, othersnore-reducing aids, such as pillows, or medicated nasal sprays.

For convenience, before further description of exemplary embodiments,certain terms employed in the specification, examples, and appendedclaims are collected here. These definitions should be read in light ofthe remainder of the disclosure and understood as by a person of skillin the art.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “access device” is an art-recognized term and includes anymedical device adapted for gaining or maintaining access to an anatomicarea. Such devices are familiar to artisans in the medical and surgicalfields. An access device may be a needle, a catheter, a cannula, atrocar, a tubing, a shunt, a drain, or an endoscope such as an otoscope,nasopharyngoscope, bronchoscope, or any other medical device suitablefor entering or remaining positioned within the preselected anatomicarea.

The terms “biocompatible polymer” and “biocompatibility” when used inrelation to polymers are art-recognized. For example, biocompatiblepolymers include polymers that are generally neither themselves toxic tothe host, nor degrade (if the polymer degrades) at a rate that producesmonomeric or oligomeric subunits or other byproducts at toxicconcentrations in the host. In certain embodiments, biodegradationgenerally involves degradation of the polymer in a host, e.g., into itsmonomeric subunits, which may be known to be effectively non-toxic.Intermediate oligomeric products resulting from such degradation mayhave different toxicological properties, however, or biodegradation mayinvolve oxidation or other biochemical reactions that generate moleculesother than monomeric subunits of the polymer. Consequently, in certainembodiments, toxicology of a biodegradable polymer intended for in vivouse, such as implantation or injection into a patient, may be determinedafter one or more toxicity analyses. It is not necessary that anysubject composition have a purity of 100% to be deemed biocompatible;indeed, it is only necessary that the subject compositions bebiocompatible as set forth above. Hence, a subject composition maycomprise polymers comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75%or even less of biocompatible polymers, e.g., including polymers andother materials and excipients described herein, and still bebiocompatible.

To determine whether a polymer or other material is biocompatible, itmay be necessary to conduct a toxicity analysis. Such assays are wellknown in the art. One example of such an assay may be performed withlive carcinoma cells, such as GT3TKB tumor cells, in the followingmanner: the sample is degraded in 1M NaOH at 37° C. until completedegradation is observed. The solution is then neutralized with 1M HCl.About 200 μL of various concentrations of the degraded sample productsare placed in 96-well tissue culture plates and seeded with humangastric carcinoma cells (GT3TKB) at 10⁴/well density. The degradedsample products are incubated with the GT3TKB cells for 48 hours. Theresults of the assay may be plotted as % relative growth vs.concentration of degraded sample in the tissue-culture well. Inaddition, polymers and formulations may also be evaluated by well-knownin vivo tests, such as subcutaneous implantations in rats to confirmthat they do not cause significant levels of irritation or inflammationat the subcutaneous implantation sites.

The term “biodegradable” is art-recognized, and includes polymers,compositions and formulations, such as those described herein, that areintended to degrade during use. Biodegradable polymers typically differfrom non-biodegradable polymers in that the former may be degradedduring use. In certain embodiments, such use involves in vivo use, suchas in vivo therapy, and in other certain embodiments, such use involvesin vitro use. In general, degradation attributable to biodegradabilityinvolves the degradation of a biodegradable polymer into its componentsubunits, or digestion, e.g., by a biochemical process, of the polymerinto smaller, non-polymeric subunits. In certain embodiments, twodifferent types of biodegradation may generally be identified. Forexample, one type of biodegradation may involve cleavage of bonds(whether covalent or otherwise) in the polymer backbone. In suchbiodegradation, monomers and oligomers typically result, and even moretypically, such biodegradation occurs by cleavage of a bond connectingone or more of subunits of a polymer. In contrast, another type ofbiodegradation may involve cleavage of a bond (whether covalent orotherwise) internal to side chain or that connects a side chain to thepolymer backbone. For example, a therapeutic agent or other chemicalmoiety attached as a side chain to the polymer backbone may be releasedby biodegradation. In certain embodiments, one or the other or bothgenerally types of biodegradation may occur during use of a polymer. Asused herein, the term “biodegradation” encompasses both general types ofbiodegradation.

The degradation rate of a biodegradable polymer often depends in part ona variety of factors, including the chemical identity of the linkageresponsible for any degradation, the molecular weight, crystallinity,biostability, and degree of cross-linking of such polymer, the physicalcharacteristics of the implant, shape and size, and the mode andlocation of administration. For example, the greater the molecularweight, the higher the degree of crystallinity, and/or the greater thebiostability, the biodegradation of any biodegradable polymer is usuallyslower. The term “biodegradable” is intended to cover materials andprocesses also termed “bioerodible”.

In certain embodiments, if the biodegradable polymer also has atherapeutic agent or other material associated with it, thebiodegradation rate of such polymer may be characterized by a releaserate of such materials. In such circumstances, the biodegradation ratemay depend on not only the chemical identity and physicalcharacteristics of the polymer, but also on the identity of any suchmaterial incorporated therein.

In certain embodiments, polymeric formulations biodegrade within aperiod that is acceptable in the desired application. In certainembodiments, such as in vivo therapy, such degradation occurs in aperiod usually less than about five years, one year, six months, threemonths, one month, fifteen days, five days, three days, or even one dayon exposure to a physiological solution with a pH between 6 and 8 havinga temperature of between 25 and 37° C. In other embodiments, the polymerdegrades in a period of between about one hour and several weeks,depending on the desired application.

The terms “comprise,” “comprising,” “include,” “including,” “have,” and“having” are used in the inclusive, open sense, meaning that additionalelements may be included. The terms “such as”, “e.g.”, as used hereinare non-limiting and are for illustrative purposes only. “Including” and“including but not limited to” are used interchangeably.

The term “drug delivery device” is an art-recognized term and refers toany medical device suitable for the application of a drug to a targetedorgan or anatomic region. The term includes those devices that transportor accomplish the instillation of the compositions towards the targetedorgan or anatomic area, even if the device itself is not formulated toinclude the composition. As an example, a needle or a catheter throughwhich the composition is inserted into an anatomic area or into a bloodvessel or other structure related to the anatomic area is understood tobe a drug delivery device. As a further example, a stent or a shunt or acatheter that has the composition included in its substance or coated onits surface is understood to be a drug delivery device.

When used with respect to a therapeutic agent or other material, theterm “sustained release” is art-recognized. For example, a subjectcomposition that releases a substance over time may exhibit sustainedrelease characteristics, in contrast to a bolus type administration inwhich the entire amount of the substance is made biologically availableat one time. For example, in particular embodiments, upon contact withbody fluids including blood, tissue fluid, lymph or the like, thepolymer matrices (formulated as provided herein and otherwise as knownto one of skill in the art) may undergo gradual degradation (e.g.,through hydrolysis) with concomitant release of any materialincorporated therein, for a sustained or extended period (as compared tothe release from a bolus). This release may result in prolonged deliveryof therapeutically effective amounts of any incorporated a therapeuticagent. Sustained release will vary in certain embodiments as describedin greater detail below.

The term “delivery agent” is an art-recognized term, and includesmolecules that facilitate the intracellular delivery of a therapeuticagent or other material. Examples of delivery agents include: sterols(e.g., cholesterol) and lipids (e.g., a cationic lipid, virosome orliposome).

The term “or” as used herein should be understood to mean “and/or”,unless the context clearly indicates otherwise.

The phrases “parenteral administration” and “administered parenterally”are art-recognized terms, and include modes of administration other thanenteral and topical administration, such as injections, and include,without limitation, intravenous, intramuscular, intrapleural,intravascular, intrapericardial, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intranasal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intra-articular, subcapsular, subarachnoid, intraspinal and intrasternalinjection and infusion.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder or condition, e.g., causing regression of the disease, disorderand/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected.

The term “fluid” is art-recognized to refer to a non-solid state ofmatter in which the atoms or molecules are free to move in relation toeach other, as in a gas or liquid. If unconstrained upon application, afluid material may flow to assume the shape of the space available toit, covering for example, the surfaces of an excisional site or the deadspace left under a flap. A fluid material may be inserted or injectedinto a limited portion of a space and then may flow to enter a largerportion of the space or its entirety. Such a material may be termed“flowable.” This term is art-recognized and includes, for example,liquid compositions that are capable of being sprayed into a site;injected with a manually operated syringe fitted with, for example, a23-gauge needle; or delivered through a catheter. Also included in theterm “flowable” are those highly viscous, “gel-like” materials at roomtemperature that may be delivered to the desired site by pouring,squeezing from a tube, or being injected with any one of thecommercially available injection devices that provide injectionpressures sufficient to propel highly viscous materials through adelivery system such as a needle or a catheter. When the polymer used isitself flowable, a composition comprising it need not include abiocompatible solvent to allow its dispersion within a body cavity.Rather, the flowable polymer may be delivered into the body cavity usinga delivery system that relies upon the native flowability of thematerial for its application to the desired tissue surfaces. Forexample, if flowable, a composition comprising polymers can be injectedto form, after injection, a temporary biomechanical barrier to coat orencapsulate internal organs or tissues, or it can be used to producecoatings for solid implantable devices. In certain instances, flowablesubject compositions have the ability to assume, over time, the shape ofthe space containing it at body temperature.

Viscosity is understood herein as it is recognized in the art to be theinternal friction of a fluid or the resistance to flow exhibited by afluid material when subjected to deformation. The degree of viscosity ofthe polymer may be adjusted by the molecular weight of the polymer andother methods for altering the physical characteristics of a specificpolymer will be evident to practitioners of ordinary skill with no morethan routine experimentation. The molecular weight of the polymer usedmay vary widely, depending on whether a rigid solid state (highermolecular weights) desirable, or whether a fluid state (lower molecularweights) is desired.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting any subject composition from one organ, or portion of thebody, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof a subject composition and not injurious to the patient. In certainembodiments, a pharmaceutically acceptable carrier is non-pyrogenic.Some examples of materials which may serve as pharmaceuticallyacceptable carriers include: (1) sugars, such as lactose, glucose andsucrose; (2) starches, such as corn starch and potato starch; (3)cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5)malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter andsuppository waxes; (9) oils, such as peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10)glycols, such as propylene glycol; (11) polyols, such as glycerin,sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyloleate and ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19)ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxiccompatible substances employed in pharmaceutical formulations.

The term “pharmaceutically acceptable salts” is art-recognized, andincludes relatively non-toxic, inorganic and organic acid addition saltsof compositions, including without limitation, therapeutic agents,excipients, other materials and the like. Examples of pharmaceuticallyacceptable salts include those derived from mineral acids, such ashydrochloric acid and sulfuric acid, and those derived from organicacids, such as ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like. Examples of suitable inorganicbases for the formation of salts include the hydroxides, carbonates, andbicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium,aluminum, zinc and the like. Salts may also be formed with suitableorganic bases, including those that are non-toxic and strong enough toform such salts. For purposes of illustration, the class of such organicbases may include mono-, di-, and trialkylamines, such as methylamine,dimethylamine, and triethylamine; mono-, di- or trihydroxyalkylaminessuch as mono-, di-, and triethanolamine; amino acids, such as arginineand lysine; guanidine; N-methylglucosamine; N-methylglucamine;L-glutamine; N-methylpiperazine; morpholine; ethylenediamine;N-benzylphenethylamine; (trihydroxymethyl)aminoethane; and the like.See, for example, J. Pharm. Sci., 66:1-19 (1977).

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The terms “therapeutic agent”, “drug”, “medicament” and “bioactivesubstance” are art-recognized and include molecules and other agentsthat are biologically, physiologically, or pharmacologically activesubstances that act locally or systemically in a patient or subject totreat a disease or condition. The terms include without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of disease orillness; or substances which affect the structure or function of thebody; or pro-drugs, which become biologically active or more activeafter they have been placed in a predetermined physiologicalenvironment.

Such agents may be acidic, basic, or salts; they may be neutralmolecules, polar molecules, or molecular complexes capable of hydrogenbonding; they may be prodrugs in the form of ethers, esters, amides andthe like that are biologically activated when administered into apatient or subject.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a therapeuticagent that, when incorporated into a polymer, produces some desiredeffect at a reasonable benefit/risk ratio applicable to any medicaltreatment. In certain embodiments, the term refers to that amountnecessary or sufficient to eliminate, reduce or maintain (e.g., preventthe spread of) a tumor or other target of a particular therapeuticregimen. The effective amount may vary depending on such factors as thedisease or condition being treated, the particular targeted constructsbeing administered, the size of the subject or the severity of thedisease or condition. One of ordinary skill in the art may empiricallydetermine the effective amount of a particular compound withoutnecessitating undue experimentation.

The term “preventing”, when used in relation to a condition, such as alocal recurrence, a disease such as cancer, a syndrome complex such asheart failure or any other medical condition, is well understood in theart, and includes administration of a composition which reduces thefrequency of, or delays the onset of, symptoms of a medical condition ina subject relative to a subject which does not receive the composition.Thus, prevention of cancer includes, for example, reducing the number ofdetectable cancerous growths in a population of patients receiving aprophylactic treatment relative to an untreated control population,and/or delaying the appearance of detectable cancerous growths in atreated population versus an untreated control population, e.g., by astatistically and/or clinically significant amount. Prevention of aninfection includes, for example, reducing the number of diagnoses of theinfection in a treated population versus an untreated controlpopulation, and/or delaying the onset of symptoms of the infection in atreated population versus an untreated control population.

“Radiosensitizer” is defined as a therapeutic agent that, uponadministration in a therapeutically effective amount, promotes thetreatment of one or more diseases or conditions that are treatable withelectromagnetic radiation. In general, radiosensitizers are intended tobe used in conjunction with electromagnetic radiation as part of aprophylactic or therapeutic treatment. Appropriate radiosensitizers touse in conjunction with treatment with the subject compositions will beknown to those of skill in the art.

“Electromagnetic radiation” as used in this specification includes, butis not limited to, radiation having the wavelength of 10⁻²⁰ to 10meters. Particular embodiments of electromagnetic radiation employ theelectromagnetic radiation of: gamma-radiation (10⁻²⁰ to 10⁻¹³ m), x-rayradiation (10⁻¹¹ to 10⁻⁹ m), ultraviolet light (10 nm to 400 nm),visible light (400 nm to 700 nm), infrared radiation (700 nm to 1.0 mm),and microwave radiation (1 mm to 30 cm).

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject compositionor other material at a site remote from the disease being treated.Administration of an agent directly into, onto or in the vicinity of alesion of the disease being treated, even if the agent is subsequentlydistributed systemically, may be termed “local” or “topical” or“regional” administration, other than directly into the central nervoussystem, e.g., by subcutaneous administration, such that it enters thepatient's system and, thus, is subject to metabolism and other likeprocesses.

In certain embodiments, a therapeutically effective amount of atherapeutic agent for in vivo use will likely depend on a number offactors, including: the rate of release of the agent from the polymermatrix, which will depend in part on the chemical and physicalcharacteristics of the polymer; the identity of the agent; the mode andmethod of administration; and any other materials incorporated in thepolymer matrix in addition to the agent.

The term “ED₅₀” is art-recognized. In certain embodiments, ED₅₀ meansthe dose of a drug which produces 50% of its maximum response or effect,or alternatively, the dose which produces a pre-determined response in50% of test subjects or preparations. The term “LD₅₀” is art-recognized.In certain embodiments, LD₅₀ means the dose of a drug which is lethal in50% of test subjects. The term “therapeutic index” is an art-recognizedterm which refers to the therapeutic index of a drug, defined asLD₅₀/ED₅₀.

The terms “incorporated” and “encapsulated” are art-recognized when usedin reference to a therapeutic agent and a polymeric composition, such asa composition disclosed herein. In certain embodiments, these termsinclude incorporating, formulating or otherwise including such agentinto a composition which allows for sustained release of such agent inthe desired application. The terms may contemplate any manner by which atherapeutic agent or other material is incorporated into a polymermatrix, including for example: attached to a monomer of such polymer (bycovalent or other binding interaction) and having such monomer be partof the polymerization to give a polymeric formulation, distributedthroughout the polymeric matrix, appended to the surface of thepolymeric matrix (by covalent or other binding interactions),encapsulated inside the polymeric matrix, etc. The term“co-incorporation” or “co-encapsulation” refers to the incorporation ofa therapeutic agent or other material and at least one other atherapeutic agent or other material in a subject composition.

More specifically, the physical form in which a therapeutic agent orother material is encapsulated in polymers may vary with the particularembodiment. For example, a therapeutic agent or other material may befirst encapsulated in a microsphere and then combined with the polymerin such a way that at least a portion of the microsphere structure ismaintained. Alternatively, a therapeutic agent or other material may besufficiently immiscible in a controlled-release polymer that it isdispersed as small droplets, rather than being dissolved, in thepolymer. Any form of encapsulation or incorporation is contemplated bythe present disclosure, in so much as the sustained release of anyencapsulated therapeutic agent or other material determines whether theform of encapsulation is sufficiently acceptable for any particular use.

The term “biocompatible plasticizer” is art-recognized, and includesmaterials which are soluble or dispersible in the controlled-releasecompositions described herein, which increase the flexibility of thepolymer matrix, and which, in the amounts employed, are biocompatible.Suitable plasticizers are well known in the art and include thosedisclosed in U.S. Pat. Nos. 2,784,127 and 4,444,933. Specificplasticizers include, by way of example, acetyl tri-n-butyl citrate (c.20 weight percent or less), acetyl trihexyl citrate (c. 20 weightpercent or less), butyl benzyl phthalate, dibutyl phthalate,dioctylphthalate, n-butyryl tri-n-hexyl citrate, diethylene glycoldibenzoate (c. 20 weight percent or less) and the like.

“Small molecule” is an art-recognized term. In certain embodiments, thisterm refers to a molecule which has a molecular weight of less thanabout 2000 amu, or less than about 1000 amu, and even less than about500 amu.

In the embodiment shown in FIG. 1, the nasal breathing assist device 1comprises generally a pair of open ended tubular elements 10 connectedtogether by a coupler element 16.

The tubular elements 10 are generally circular in cross section andextend a distance along tube axes X1 and X2 from first ends 12 to secondends 14. Preferably the tubular elements taper linearly from arelatively large diameter cross section along the tube axes X1 and X2 toa relatively smaller diameter cross section from the first end 12 to thesecond end 14. The taper may be other than linear, for example,contoured to correspond generally to the taper inside the user'snostrils. First ends 12 also connect to the coupler element 16. In theillustrated form, the tubular elements 10 are conic-frustums, but othershapes may be used. For example, instead of circular cross sections, thetubular elements could have elliptical or other shaped cross sections.Further, instead of the inner diameter tapering monotonically from thelarge end to the small end, it could decrease initially, become larger,then decrease again.

The tubular elements 10 may also include at least one passageway 18extending through the walls of the tubular elements transverse to thetube axes X1 and X2. The passageways 18 may be circular, elliptical, orelongated at least in part in the direction of the tube axes.Alternately, the passageways can be elongated in a direction extendingcircumferentially around the tube axes.

The coupler element 16 is a resilient, nominally curved strut whichmaintains the tubular elements spaced apart, with axes X1 and X2 in asubstantially parallel relationship, and in substantially a commonplane. The coupler element may be made of resilient, semi-rigid, orrigid material.

Grooves 19 inside of tubular elements are an additional feature whichmay be used to receive medication (nasal cream) before inserting innasal passage so as not to irritate the skin inside the nasal passage,this allows the medication to be effective without contacting the nasalpassage.

As shown in FIG. 2, coupler element 16 maintains a nominal distance Dbetween the tubular elements 10 that generally corresponds to thedistance between the user's nostrils. In this embodiment, the couplerelement extends in a plane that is essentially parallel to tube axes X1and X2. As shown in FIGS. 3A and 3B, the resistance of coupler element16 permits the axes X1 and X2 to be offset from an axis X₀ by angle A.Angle A can be as much as 15° or greater. Furthermore, in thisembodiment, coupler element 16 permits relative flexing motion of thedevice about an axis, substantially perpendicular to the tube axes X1and X2.

In a preferred embodiment shown in FIG. 4A, device 1′ has couplerelement 16′ which extends between first ends 12. The central axis ofcoupler element 16′ lies in a plane that is substantially perpendicularto the tube axes X1 and X2. In this embodiment, coupler element 16′permits relative flexing motion of device 1′ so that axes X1 and X2remain substantially parallel, but separation S of those axes varies toaccommodate spacing of the nostrils.

Radially extending tab supports 20 extend from first ends 12 and connectto coupler element 16. Tabs 22 extend from tab supports 20 a distance Min the direction of the central axis to distal ends of the tabs. Tabs 22are preferably made of non-resiliently deformable materials, forexample, metal including copper, aluminum, and etc. The tab supports 20may be made of the same or different materials as that used for the tabs22. In use, tabs 22 remain outside the user's nostrils, and, acting asclips, help secure the device in the nostrils. The tabs 22 also functionas a stop which prevent the device from being wholly inserted into auser's nostril.

In another preferred embodiment, as shown in FIG. 4B, the tabs 22 aresubstantially S-shaped, and includes a distal curved portion 23 distalfrom the first end 12. The distal curved portion 23 defines a relativelysmall gap G with an outer surface of the tubular element. The tabs 22are constructed such that the small gap G is adapted to receive alateral wall of a user's nose, and the tabs 22 are adapted to clip onthe lateral wall of the user's nose. In one preferred embodiment, thetab 22 includes at least one relatively small protrusion 50 extendingfrom the distal curved portion 23 toward the tubular element 10, as bestshown in FIG. 4B and FIG. 5B. Alternatively, the relatively smallprotrusion 50 may extend from the outer surface of the tubular element10 toward the distal curved portion 23 of the tab 22. In anotheralternate embodiment, the tab 22 includes protrusions 50 extending fromthe distal curved portion 23 toward the tubular element 10, and thetubular element 10 also includes protrusions opposing to the protrusionsof the tab 22. In the embodiment shown in FIG. 4A, the protrusions 50extends from a distal end of the tab 22 toward the tubular element 10.The small protrusion helps to secure the device in the user's nostrils.

FIGS. 5A-5E show other embodiments of nasal breathing assist devices. InFIG. 5A, device 1″ has a tubular element 10 extending along a tube axisX between a relatively large diameter first end 12 and tapering toward arelatively smaller diameter second end 14. As previously described,tubular element 10 may have passageways 18 extending through the wallsof the tubular elements transverse to tube axis X.

As shown in the embodiment in FIG. 5B, radially extending tab support 20extends from first end 12. The substantially S-shaped non-resilient tab22 extends from tab support 20 a distance M in the direction of axis Xtoward second end 14. FIG. 5C illustrates another preferred embodiment,in which the device includes a stop member 52 extending radially andoutwardly from the first end 12 of the tubular element to a distal end.The stop member 52 is adapted to engage with an open end of a user'snostril to prevent the device from being wholly inserted into thenostril when the device is in use. In an alternate embodiment, as shownin FIG. 5D, the stop member may further include a protrusion extendingfrom the distal end of the stop member toward the second 14 of thetubular element 10. In another alternate embodiment, as shown in FIG.5E, the substantially S-shaped non-resilient tab 22, the tab support 20,and the tubular element 10 are integrally constructed. In use, theprotrusion remains outside the user's nostril, and, acting as a clip,helps secure the device in the nostril. Device 1″ of FIGS. 5A-5E may beused singly or as a pair. The stop member 52 may also be employed in theembodiments having a pair of tubular elements connected by a couplerelement.

In another preferred embodiment, the tab 22 has an inner surface, whichfaces the tubular element and is at least partially coated with adhesive98, as shown in FIGS. 10A and 10B. The tab 22 is also preferablynon-resiliently deformable. In use, after the device is inserted into auser's nostrils and the tab 22 is pressed against the outer surface theuser's nose, the tab 22 keeps in contact with the outer surface of theuser's nose. The adhesive coating increases the friction between the tab22 and the outer surface of the user's nose, and make the tab to stickto the outer surface of the user's nose, thus increasing the stabilityof the device within the user's nose. The adhesive coating of the innersurface of the tab helps to maintain the device within a user's nose,preventing the device from being knocked off during sleep, sports, orother activities.

FIG. 6 shows a filter 30 which may be used with the nasal breathingassist device. The filter 30 includes a filter medium, preferably apaper, a metal or plastic mesh coated with absorbent materials, spanninga frame 32. The frame 32 is preferably contoured to fit in an open-facedinner channel 36 defined in the tubular element 10. In a preferredembodiment, the tubular element 10 includes at least one relativelysmall protrusion 38 extending radially from an inner surface of theinner channel 36. The frame 32 of the filter 30 is adapted to snap-fitover the protrusion 38 into the inner channel 36 and is retained by theprotrusion 38, thereby the filter 30 cannot slip out of the tubularelement 10 when the nasal breathing assist device is in use. A filtermay be secured to a device in several other ways, such as by adhesive,snap-fitting, press-fitting, integral molding, twist-locking, slidinginto groove(s) 19, and/or by use of hook-and-loop fasteners (such asVELCRO® brand fasteners).

FIG. 7 illustrates a cross-sectional view of one tubular element 10 inaccordance with one preferred embodiment of the invention. As shown inFIG. 7, the protrusion 38 extends throughout an inner circumference atthe first end 12 (the end with a relatively large diameter) of the innerchannel 36. The filter 30 is snap-plugged into the channel 36 from thefirst end of the channel 36, and because the diameter of the channel 36tapers from the first end to the second end, the filter can be securedby the inner surface of the channel 36 and the protrusion 38. Theprotrusion 38 is relatively small, so that the filter 36 can by easilyremoved and replaced. FIG. 8 shows a schematic view of the filters 30together with a nasal breathing assist device. Each tubular element 10includes relatively small protrusions 38 securing the filter 30 at thefirst end of the tubular element 10. The filter 30 is preferablypositioned at one of the two ends of the tubular element 10, so that thefilter 30 can be easily removed and replaced, but the filter 30 also canbe positioned at a place between the two ends and secured by protrusionsextending radially adjacent that place.

FIG. 9 illustrates another preferred embodiment of the presentinvention. As shown in FIG. 9, The device further includes at least oneremovable medication carrier 60 which may include a medium adapted tobear a therapeutic agent. The removable carrier 60 preferably includes aframe tapering from a first end to a second end. The frame includes twoopposite edges 62. The tubular element 10 further defines two opposingchannels 64 on an inner surface of the tubular element 10. The twoopposing channels 64 extend substantially in the same direction as thecentral axis and are adapted to receive the two opposite edges 62 ofsaid removable carrier 60. The frame of the removable medication carrier60 may be constructed with other shapes, and the tubular element maydefine corresponding channels or other mechanism for receiving the frameof the carrier 60. The therapeutic agent may be medications, forexample, antibiotics, for treating chronic sinusitis or other nasaldiseases.

In alternative embodiments, as illustrated in FIGS. 10A and 10B, thefilter is a liner filter (as denoted by number 80 in FIGS. 10A and 10B)including a conic-shaped liner portion 82 extending between two ends 84and 86. One end has a relatively large diameter and the other end has arelatively small diameter. In the embodiment shown in FIG. 10A, therelatively large end 84 is a closed end having a filter medium spanningthe circumference of the end of the liner portion, and the other end 86is an opened end. In an alternative form, as shown in FIG. 10B, thefilter medium is attached to the relatively small end 86, and therelative large end is an open-faced end.

The liner portion 82, preferably but not necessarily, is constructed bythe filter medium. The filter 80 preferably but not necessarily is madefrom a unitary sheet of a filter medium by a molding process. The filter80 is sized to fit in the open-faced inner channel 36 defined in thetubular element 10. The tubular element 10 may include at least onerelatively small protrusion extending radially from an inner surface ofthe inner channel 36 at the relatively large end of the tubular elementfor preventing the liner filter 80 from slipping out of the channel 36of the tubular element 10. In use, the liner filter 80 is inserted intoand retained in the inner channel 36 of the tubular element 10. Theliner filter 80 can be easily removed from the inner channel 36, and canbe replaced or cleaned.

The filter medium is constructed to filter pollen, dust, mold, and/orother particles that may cause allergic reactions or other diseases ordiscomfort. In an alternative form, the filter medium is preferably madefrom a material that can be coated with medications, particularly,medications for treating nasal diseases. Exemplary medications includedecongestants, antihistamine, and antibiotic.

The filters as illustrated in FIGS. 6-8, the medication carriers shownin FIG. 9, and the liner filters as shown in FIGS. 10A and 10B can beused with nasal breathing assist devices, which have one tubular elementor have a pair of tubular elements connected by a strut, as described inthe previous embodiments. The nasal breathing assist devices can bedisposable or reusable. The reusable devices can be easily cleaned byrinsing, washing, or scrubbing with water, such as hot tap water, withsoap and water, with isopropyl alcohol, or by steam sterilizing (such asby microwave sterilizer), autoclaving, or boiling in tap water.

The device can be made of rigid, semi-resilient, or resilient materials.In one preferred embodiment, the tubular element 10 includes at leastone stiffening element 90 embedded in or attached to the tubularelement. The stiffening element 90 is preferably made from a materialwith a higher hardness value than the rest part of the tubular element10. In one preferred form, as shown in FIG. 11A, the stiffening element90 includes two rigid rings 92, 94 extending about the central axis ofthe tubular element 10 and embedded in the conic wall of the tubularelement 10, one of the two rings, for example, the ring 92, preferablyembedded at or near the relatively large end of the tubular element 10,and the other (ring 94) embedded at or near the relatively small end ofthe tubular element 10. The device could include more than twostiffening rings, and/or other shape stiffening parts embedded in theconic wall of the tubular element 10. Alternatively, the stiffeningelement 90 also can be attached to the inner surface or outer surface ofthe tubular element 10. The stiffening element prevents the tubularelement 10 from collapse when under pressure and maintain opening of thenasal passage in severe cases, for example, pathologic nasal valvecollapse, septal deviation, and other types of nasal congestion orobstruction. The stiffening element also increases the resilience of thetubular element 10 and the stability of the tubular element 10 within auser's nostrils.

In another preferred embodiment, as shown in FIG. 11B, the stiffeningelement 90 includes an elongated wire embedded within the tubularelement 10 and the tab 22.

In one preferred embodiment, part of the device is made from anon-resiliently deformable material, for example, aluminum. Preferably,the tabs 22 shown in FIGS. 4A-5E are made from a non-resilientlydeformable material. In another preferred embodiment, as shown in FIG.11B, an elongated metal wire is embedded within the tubular element 10and the tab 22. In one preferred form, the wire is non-resilientlydeformable, enabling the tab 22 non-resiliently deformable. In anotherpreferred form, the wire is made from a resilient material, enabling thetab 22 resiliently deformable. In use, after the device is inserted to auser's nostrils, the user can force the tab 22 toward the outer surfaceof the user's nose to allow the tab 22 to touch the outer surface of theuser's nose. The tab 22 will stay in contact with the outer surface ofthe user's nose, thus preventing the device from slipping out of theuser's nose.

In a further preferred embodiment, at least part of the device is madefrom a shape memory material, such as a nickel-titanium alloy. Forexample, the device may have one shape under room temperature, and afterthe device is inserted into the user's nostrils, where the temperatureis normally higher than the room temperature, the device returns to itsoriginal shape that fit the contour of the inside of the user'snostrils. The device may also be coated, or embedded with medicationsfor treating nasal diseases, or other diseases, such as skin or mucousdiseases.

The nasal breathing assist device is inserted in the user's nostrils, asshown in FIG. 12, usually at bedtime. The tubular elements maintain opennasal passages during sleeping, which allow the patient to obtainsufficient airflow through the nose only, rather than supplementing theair supply through the mouth. The filters can be made to absorb or holdpollen, dust, particles in smoke and smog fumes, nicotine in tobaccosmoke, obnoxious odors, and other irritating elements.

FIGS. 13-21 depict nasal devices embodying additional features. Theseadditional features may or may not be combined, as desired, withfeatures described elsewhere in this disclosure.

FIG. 13 depicts a device 100 having a roughly frustoconical, dome-like,or cylindrical shape. The device includes a wall having a first end 12and a second end 14. The wall may define one or more passageways 18 asdescribed previously. The first and second ends define openings thatallow passage of air or the positioning of insert(s), as describedpreviously. The diameter, diagonal measure, and/or cross-sectional areaof the second end may be smaller than that of the first end, tofacilitate positioning of the device in, for example, a nostril. Thefirst end portion of the wall defines a break 130, so that the first endopening is not completely encircled. The break may be continuous with apassageway, as shown. The break may increase the flexibility of thedevice. The second end need not define a break and may insteadcompletely encircle the second end opening. The device may also includea foot 140 protruding from the first end. The foot may protrude outwardas shown in FIG. 13, downward as shown in FIG. 14, or at intermediateangles. The foot may be rigidly positioned or may be flexible so that itcan be positioned selectively. The foot may be so formed as to permitits remaining at a selected orientation, such as by embedding a metalwire or ribbon in the foot. The foot itself may be malleable to permitadjustment.

FIG. 15 depicts another embodiment of a device in which the second enddefines a break 130, and the device includes a tab support 20. Thedevice may further include a tab (not shown), which may be used to clipthe device to a subject's nose, for example.

FIG. 16 depicts yet another embodiment of a device in which the break130 is positioned at some distance away from feature 150 (such as foot140 or tab support 20). The break may, but need not, be adjacent feature150.

FIG. 17 depicts an embodiment of a device having more then one break 130in the first end of the wall. Any desired number of breaks may beprovided in the first end. FIG. 17 also shows grooves or ribs 160, whichmay be thinned or thickened portions of the wall, respectively. Ribs mayalso be strips of material (such as metal or plastic) attached to orembedded in the wall.

FIG. 18 depicts an embodiment of a device in which the first end has oneor more thinned or webbed portions 170. Like the breaks describedpreviously, the thinned or webbed portions may provide the device withgreater flexibility. The thinned or webbed portions may be a thinnerportion of the same material as the device's wall or may be made of adifferent material that is either thinner than and/or is more flexiblethan, the material of the rest of the first end.

FIG. 19 depicts an embodiment of a device having attached to it a tether180. The tether may be a pull string or other appendage to facilitatepositioning and/or removal of the device. The tether may be a cannula,i.e., a tube that carries a fluid or gas, such as air, oxygen-enrichedair, oxygen, etc.

FIG. 20 shows devices 100 incorporated with a nasal cannula 190 fordelivering gases such as air, oxygen, or oxygen-enriched air to asubject's nostrils. The devices depicted herein can also serve asadapters to receive more standard nasal cannula prongs to prevent themfrom contacting, irritating, eroding, or otherwise compromising nasalsurfaces.

A connector 200 may connect devices 100. The connector may be rigid orpliable. It may be so shaped as to avoid contacting nasal tissue inorder to prevent irritation or damage to the tissue. Alternatively, asshown in FIG. 21, there may be no connection between the devices; eachdevice receives a cannula (or other tether).

As described earlier, devices may be given circular, elliptical, orother cross sections. This may be done to ensure that when a device isinserted into an anatomic space, such as a nostril, that space'sgeometry changes. The device may also be made of material sufficientlystiff to overcome the anatomic space's shape. In other words, the devicemay be intentionally designed not to conform the anatomy but to alterit. By changing the geometry, specifically, by increasing the anatomicspace's volume, air flow through the space may be increased.

The devices disclosed herein can be used to aid in the administration ofnasally supplied drugs, medications, herbal preparations, aromatherapysubstances, homeopathic substances, and other substances, either atbedtime or during the day, for example, using a medication carrierinserted in the tubular element to deliver medications through the nose,or by coating, embedding, or integrally forming a device with thesubstance to be delivered. The nasal breathing assist device can also beused with other conventional devices to supply drugs and medications;for example, the user can insert the device into the nose, and spray anasal medication, or moisture mist agent into the nose. The passagewaysin the device act to help circulate the medication or agent within thenasal passageways by keeping the nasal passages open.

Possible biologically active agents include without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of disease orillness; substances that affect the structure or function of the body;herbal preparations; aromatherapy substances; or homeopathic substances.

The therapeutic agents are used in amounts that are therapeuticallyeffective, which varies widely depending largely on the particular agentbeing used. The amount of agent incorporated into the composition alsodepends upon the desired release profile, the concentration of the agentrequired for a biological effect, and the length of time that thebiologically active substance has to be released for treatment. Incertain embodiments, the biologically active substance may be blendedwith a polymer matrix at different loading levels, in one embodiment atroom temperature and without the need for an organic solvent. In otherembodiments, the compositions may be formulated as microspheres.

There is no critical upper limit on the amount of therapeutic agentincorporated except for that of an acceptable solution or dispersionviscosity to maintain the physical characteristics desired for thecomposition. The lower limit of the agent incorporated into the polymersystem is dependent upon the activity of the drug and the length of timeneeded for treatment. Thus, the amount of the agent should not be sosmall that it fails to produce the desired physiological effect, nor solarge that the agent is released in an uncontrollable manner. Typically,within these limits, amounts of the therapeutic agents from about 1% upto about 60% may be incorporated into the present delivery systems.However, lesser amounts may be used to achieve efficacious levels oftreatment for agent that are particularly potent.

Specific types of biologically active agents include, either directly orafter appropriate modification, without limitation: anti-angiogenesisfactors, antiinfectives such as antibiotics and antiviral agents;analgesics and analgesic combinations; anorexics; antihelmintics;antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants;antidiuretic agents; antidiarrheals; antihistamines; antiinflammatoryagents; antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antiproliferatives; antimitotics; antimetabolitecompounds; angiostatics; angiostatic steroids; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; catecholamines; diuretics;vasodilators including general coronary, peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; growth factors, hormones such as estradiol andother steroids, including corticosteroids; hypnotics;immunosuppressives; steroids; corticosteroids; glucocorticoids; musclerelaxants; parasympatholytics; psychostimulants; sedatives; andtranquilizers; and naturally derived or genetically engineered proteins,polysaccharides, glycoproteins, lipoproteins, interferons, cytokines,chemotherapeutic agents and other anti-neoplastics, antibiotics,anti-virals, anti-fungals, anti-inflammatories, anticoagulants,lymphokines, or antigenic materials.

To illustrate further, other types of biologically active agents thatmay be used, either directly or after appropriate modification, includepeptide, proteins or other biopolymers, e.g., interferons, interleukins,tumor necrosis factor, nerve growth factor (NGF), brain-derivedneurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5(NT-4/5), ciliary neurotrophic factor (CNTF), glial cell line-derivedneurotrophic factor (GDNF), cholinergic differentiation factor/Leukemiainhibitory factor (CDF/LIF), epidermal growth factor (EGF), insulin-likegrowth factor (IGF), basic fibroblast growth factor (bFGF),platelet-derived growth factor (PDGF), erythropoietin, growth hormone,Substance-P, neurotensin, insulin, erythropoietin, albumin, transferrin,and other protein biological response modifiers.

Other examples of biologically active agents that may be used eitherdirectly or after appropriate modification include acebutolol,acetaminophen, acetohydoxamic acid, acetophenazine, acyclovir,adrenocorticoids, allopurinol, alprazolam, aluminum hydroxide,amantadine, ambenonium, amiloride, aminobenzoate potassium, amobarbital,amoxicillin, amphetamine, ampicillin, androgens, anesthetics,anticoagulants, anticonvulsants-dione type, antithyroid medicine,appetite suppressants, aspirin, atenolol, atropine, azatadine,bacampicillin, baclofen, beclomethasone, belladonna,bendroflumethiazide, benzoyl peroxide, benzthiazide, benztropine,betamethasone, betha nechol, biperiden, bisacodyl, bromocriptine,bromodiphenhydramine, brompheniramine, buclizine, bumetanide, busulfan,butabarbital, butaperazine, caffeine, calcium carbonate, captopril,carbamazepine, carbenicillin, carbidopa & levodopa, carbinoxamineinhibitors, carbonic anhydsase, carisoprodol, carphenazine, cascara,cefaclor, cefadroxil, cephalexin, cephradine, chlophedianol, chloralhydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine,chlorothiazide, chlorotrianisene, chlorpheniramine, 6× chlorpromazine,chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone,cholestyramine, cimetidine, cinoxacin, clemastine, clidinium,clindamycin, clofibrate, clomiphere, clonidine, clorazepate,cloxacillin, colochicine, coloestipol, conjugated estrogen,contraceptives, cortisone, cromolyn, cyclacillin, cyclandelate,cyclizine, cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine,cyproheptadine, danazol, danthron, dantrolene, dapsone,dextroamphetamine, dexamethasone, dexchlorpheniramine, dextromethorphan,diazepan, dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal,digitalis, diltiazen, dimenhydrinate, dimethindene, diphenhydramine,diphenidol, diphenoxylate & atrophive, diphenylopyraline, dipyradamole,disopyramide, disulfiram, divalporex, docusate calcium, docusatepotassium, docusate sodium, doxyloamine, dronabinol ephedrine,epinephrine, ergoloidmesylates, ergonovine, ergotamine, erythromycins,esterified estrogens, estradiol, estrogen, estrone, estropipute,etharynic acid, ethchlorvynol, ethinyl estradiol, ethopropazine,ethosaximide, ethotoin, fenoprofen, ferrous fumarate, ferrous gluconate,ferrous sulfate, flavoxate, flecainide, fluphenazine, fluprednisolone,flurazepam, folic acid, furosemide, gemfibrozil, glipizide, glyburide,glycopyrrolate, gold compounds, griseofuwin, guaifenesin, guanabenz,guanadrel, guanethidine, halazepam, haloperidol, hetacillin,hexobarbital, hydralazine, hydrochlorothiazide, hydrocortisone(cortisol), hydroflunethiazide, hydroxychloroquine, hydroxyzine,hyoscyamine, ibuprofen, indapamide, indomethacin, insulin, iofoquinol,iron-polysaccharide, isoetharine, isoniazid, isopropamide isoproterenol,isotretinoin, isoxsuprine, kaolin & pectin, ketoconazole, lactulose,levodopa, lincomycin liothyronine, liotrix, lithium, loperamide,lorazepam, magnesium hydroxide, magnesium sulfate, magnesiumtrisilicate, maprotiline, meclizine, meclofenamate, medroxyproyesterone,melenamic acid, melphalan, mephenytoin, mephobarbital, meprobamate,mercaptopurine, mesoridazine, metaproterenol, metaxalone,methamphetamine, methaqualone, metharbital, methenamine, methicillin,methocarbamol, methotrexate, methsuximide, methyclothinzide,methylcellulos, methyldopa, methylergonovine, methylphenidate,methylprednisolone, methysergide, metoclopramide, metolazone,metoprolol, metronidazole, minoxidil, mitotane, monamine oxidaseinhibitors, nadolol, nafcillin, nalidixic acid, naproxen, narcoticanalgesics, neomycin, neostigmine, niacin, nicotine, nifedipine,nitrates, nitrofurantoin, nomifensine, norethindrone, norethindroneacetate, norgestrel, nylidrin, nystatin, orphenadrine, oxacillin,oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone, pancrelipase,pantothenic acid, papaverine, para-aminosalicylic acid, paramethasone,paregoric, pemoline, penicillamine, penicillin, penicillin-v,pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine,phenobarbital, phenolphthalein, phenprocoumon, phensuximide,phenylbutazone, phenylephrine, phenylpropanolamine, phenyl toloxamine,phenytoin, pilocarpine, pindolol, piper acetazine, piroxicam, poloxamer,polycarbophil calcium, polythiazide, potassium supplements, pruzepam,prazosin, prednisolone, prednisone, primidone, probenecid, probucol,procainamide, procarbazine, prochlorperazine, procyclidine, promazine,promethazine, propantheline, propranolol, pseudoephedrine, psoralens,psyllium, pyridostigmine, pyrodoxine, pyrilamine, pyrvinium, quinestrol,quinethazone, quinidine, quinine, ranitidine, rauwolfia alkaloids,riboflavin, rifampin, ritodrine, salicylates, scopolamine, secobarbital,senna, sannosides a & b, simethicone, sodium bicarbonate, sodiumphosphate, sodium fluoride, spironolactone, sucrulfate, sulfacytine,sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole,sulindac, talbutal, tamazepam, terbutaline, terfenadine, terphinhydrate,teracyclines, thiabendazole, thiamine, thioridazine, thiothixene,thyroblobulin, thyroid, thyroxine, ticarcillin, timolol, tocainide,tolazamide, tolbutamide, tolmetin trozodone, tretinoin, triamcinolone,trianterene, triazolam, trichlormethiazide, tricyclic antidepressants,tridhexethyl, trifluoperazine, triflupromazine, trihexyphenidyl,trimeprazine, trimethobenzamine, trimethoprim, tripclennamine,triprolidine, valproic acid, verapamil, vitamin A, vitamin B-12, vitaminC, vitamin D, vitamin E, vitamin K, xanthine, parathyroid hormone,enkephalins, and endorphins.

To illustrate further, antimetabolites may be used as upon appropriatemodification if necessary, including without limitation methotrexate,5-fluorouracil, cytosine arabinoside (ara-C), 5-azacytidine,6-mercaptopurine, 6-thioguanine, and fludarabine phosphate. Antitumorantibiotics may include but are not limited to doxorubicin,daunorubicin, dactinomycin, bleomycin, mitomycin C, plicamycin,idarubicin, and mitoxantrone. Vinca alkaloids and epipodophyllotoxinsmay include, but are not limited to vincristine, vinblastine, vindesine,etoposide, and teniposide. Nitrosoureas, including carmustine,lomustine, semustine and streptozocin, may also be prodrugs, uponappropriate modification if necessary. Hormonal therapeutics may also beprodrugs, upon appropriate modification if necessary, such ascorticosteriods (cortisone acetate, hydrocortisone, prednisone,prednisolone, methyl prednisolone dexamethasone, and fluocinoloneacetonide), estrogens, (diethylstibesterol, estradiol, esterifiedestrogens, conjugated estrogen, chlorotiasnene), progestins(medroxyprogesterone acetate, hydroxy progesterone caproate, megestrolacetate), antiestrogens (tamoxifen), aromastase inhibitors(aminoglutethimide), androgens (testosterone propionate,methyltestosterone, fluoxymesterone, testolactone), antiandrogens(flutamide), LHRH analogues (leuprolide acetate), and endocrines forprostate cancer (ketoconazole). Antitumor drugs that are radiationenhancers may also be used as prodrugs, upon appropriate modification ifnecessary. Examples of such biologically active agents include, forexample, the chemotherapeutic agents 5′-fluorouracil, mitomycin,cisplatin and its derivatives, taxol, bleomycins, daunomycins, andmethamycins. Antibiotics may be used as prodrugs as well, uponappropriate modification if necessary, and they are well known to thoseof skill in the art, and include, for example, penicillins,cephalosporins, tetracyclines, ampicillin, aureothicin, bacitracin,chloramphenicol, cycloserine, erythromycin, gentamicin, gramacidins,kanamycins, neomycins, streptomycins, tobramycin, and vancomycin.

Other agents, upon appropriate modification if necessary, which may beused include those presently classified as investigational drugs, andcan include, but are not limited to alkylating agents such as NimustineAZQ, BZQ, cyclodisone, DADAG, CB10-227, CY233, DABIS maleate, EDMN,Fotemustine, Hepsulfam, Hexamethylmelamine, Mafosamide, MDMS, PCNU,Spiromustine, TA-077, TCNU and Temozolomide; antimetabolites, such asacivicin, Azacytidine, 5-aza-deoxycytidine, A-TDA, Benzylidene glucose,Carbetimer, CB3717, Deazaguanine mesylate, DODOX, Doxifluridine,DUP-785, 10-EDAM, Fazarabine, Fludarabine, MZPES, MMPR, PALA, PLAC,TCAR, TMQ, TNC-P and Piritrexim; antitumor antibodies, such as AMPAS,BWA770U, BWA773U, BWA502U, Amonafide, m-AMSA, CI-921, Datelliptium,Mitonafide, Piroxantrone, Aclarubicin, Cytorhodin, Epirubicin,esorubicin, Idarubicin, Iodo-doxorubicin, Marcellomycin, Morpholinoanthracyclines, Pirarubicin, and SM-5887; microtubule spindleinhibitors, such as Amphethinile, Navelbine, and Taxol; thealkyl-lysophospholipids, such as BM41-440, ET-18-OCH3, andHexacyclophosphocholine; metallic compounds, such as Gallium Nitrate,CL286558, CL287110, Cycloplatam, DWA2114R, NK121, Iproplatin,Oxaliplatin, Spiroplatin, Spirogermanium, and Titanium compounds; andnovel compounds such as, for example, Aphidoicolin glycinate, Ambazone,BSO, Caracemide, DSG, Didemnin, B, DMFO, Elsamicin, Espertatrucin,Flavone acetic acid, HMBA, HHT, ICRF-187, Iododeoxyuridine, Ipomeanol,Liblomycin, Lonidamine, LY186641, MAP, MTQ, Merabarone SK&F104864,Suramin, Tallysomycin, Teniposide, THU and WR2721; and Toremifene,Trilosane, and zindoxifene.

In certain aspects, controlled-release compositions, upon contact with amucous membrane or secretions therefrom, release a therapeutic substanceover a sustained or extended period (as compared to the release from anisotonic saline solution). Such a system may result in prolongeddelivery (over, for example, 2 to 4,000 hours, even 4 to 1500 hours) ofeffective amounts (e.g., 0.00001 mg/kg/hour to 10 mg/kg/hour) of thedrug. This dosage form may be administered as is necessary depending onthe subject being treated, the severity of the affliction, the judgmentof the prescribing physician, and the like.

For treatment of diseases or conditions by drug delivery through thenasaopharyngeal mucous membrane, controlled-release compositions areadapted for transmucosal administration. As used herein, the term“anatomic area” refers to an area of nasal or nasopharyngeal anatomy. Incertain embodiments, the pharmaceutical compositions are understood toexert their effect in part by contact with a portion of the anatomicarea being treated. Contact refers to a physical touching, eitherdirectly with the subject composition being applied without interveningbarrier to the anatomic area being treated, or indirectly, where thesubject composition is applied to or is formed on a surface of aninterposed material, passing through to come into direct contact withthe anatomic area being treated. Contact, as used herein, includes thosesituations where the pharmaceutical compounds are initially positionedto contact the anatomic area being treated, and those situations wherethe controlled-release compositions are initially positioned inproximity to the anatomic area being treated without contacting it, andsubsequently move, migrate, flow, spread, or are transported to enterinto contact with the anatomic area being treated.

Contact may include partial contacts, wherein the pharmaceuticalcompounds only contact a portion of the anatomic area being treated, orthe edge or periphery or margin of the anatomic area being treated.Contact of the pharmaceutical compounds with the anatomic area beingtreated occurs from a local rather than systemic administration of saidcompounds, as these terms are defined hereinafter. The composition maybe formed as a flowable material, insertable into the anatomic area. Avariety of devices and methods for inserting the composition into thepreselected anatomic area will be familiar to practitioners of ordinaryskill in the art, for example infusion, injection, topical application,spraying, painting, coating, formed gel placement, and others. Thecomposition, alternatively, may be formed as a solid object implantablein the anatomic area, or as a film or mesh that may be used to cover asegment of the area. A variety of techniques for implanting solidobjects in relevant anatomic areas will be likewise familiar topractitioners of ordinary skill in the art.

Some examples of sustained release devices and compositions aredescribed in U.S. Pat. Nos. 5,618,563, 5,792,753, 5,942,241, 5,985,850,6,096,728, 6,214,387, 6,217,911, 6,248,345, 6,335,035, 6,346,519,6,426,339, 6,428,804, 6,451,335, 6,511,958, 6,514,514, 6,514,516,6,521,259, 6,524,606, 6,524,607, 6,527,760, 6,528,097, 6,528,107,6,534,081, 6,565,534, 6,582,715, 6,590,059, and 6,699,471; and in U.S.Patent Application Publication Nos. US 2003/0139811 A1 and US2003/0093157 A1; and in PCT Publication No. WO/0061152 A1. All of thesedocuments are hereby incorporated herein by this reference.

In some embodiments, the polymer composition may be a flexible orflowable material. When the polymer used is itself flowable, the polymercomposition, even when viscous, need not include a biocompatible solventto be flowable, although trace or residual amounts of biocompatiblesolvents may still be present.

In certain embodiments, a fluid polymer may be especially suitable forthe transmucosal delivery of therapeutics. A fluid material may beadapted for injection or instillation into a tissue mass or into anactual or potential space. Certain types of fluid polymers may be termedflowable. A flowable material, often capable of assuming the shape ofthe contours of an irregular space, may be delivered to a portion of anactual or potential space to flow therefrom into a larger portion of thespace. In this way, the flowable material may come to coat an entirepost-operative surgical site after being inserted through an edge of anincision or after being instilled through a drain or catheter left inthe surgical bed. Alternatively, if the flowable material is insertedunder pressure through a device such as a needle or a catheter, it mayperform hydrodissection, thus opening up a potential space andsimultaneously coating the space with polymer. Such potential spacessuitable for hydrodissection may be found in various identifiableanatomic areas in the nose or nasopharynx. A flowable polymer may beparticularly adapted for instillation through a needle, catheter orother delivery device such as an endoscope, since its flowablecharacteristics allow it to reach surfaces that extend beyond theimmediate reach of the delivery device. A flowable polymer in a highlyfluid state may be suitable for injection through needles or cathetersinto tissue masses, such as tumors or margins of resection sites.Physical properties of polymers may be adjusted to achieve a desirablestate of fluidity or flowability by modification of their chemicalcomponents and crosslinking, using methods familiar to practitioners ofordinary skill in the art.

A flexible polymer may be used in the fabrication of a solid article.Flexibility involves having the capacity to be repeatedly bent andrestored to its original shape. Solid articles made from flexiblepolymers are adapted for placement in anatomic areas where they willencounter the motion of adjacent organs or body walls. Certain areas ofmotion are familiar to practitioners dealing with nasal ornasopharyngeal problems. A flexible solid article can thus besufficiently deformed by those moving tissues that it does not causetissue damage. Flexibility is particularly advantageous where a solidarticle might be dislodged from its original position and therebyencounter an unanticipated moving structure; flexibility may allow thesolid article to bend out of the way of the moving structure instead ofinjuring it. Solid articles may be formed as films, meshes, sheets,tubes, or any other shape appropriate to the dimensions and functionalrequirements of the particular anatomic area. Physical properties ofpolymers may be adjusted to attain a desirable degree of flexibility bymodification of the chemical components and crosslinking thereof, usingmethods familiar to practitioners of ordinary skill in the art.

While it is possible that the biocompatible polymer or the biologicallyactive agent may be dissolved in a small quantity of a solvent that isnon-toxic to more efficiently produce an amorphous, monolithicdistribution or a fine dispersion of the biologically active agent inthe flexible or flowable composition, it is an advantage that, in anembodiment, no solvent is needed to form a flowable composition.Moreover, the use of solvents may be avoided because, once a polymercomposition containing solvent is placed totally or partially within thebody, the solvent dissipates or diffuses away from the polymer and mustbe processed and eliminated by the body, placing an extra burden on thebody's clearance ability at a time when the illness (and/or othertreatments for the illness) may have already deleteriously affected it.

However, when a solvent is used to facilitate mixing or to maintain theflowability of the polymer composition, it should be non-toxic,otherwise biocompatible, and should be used in relatively small amounts.Solvents that are toxic clearly should not be used in any material to beplaced even partially within a living body. Such a solvent also must notcause substantial tissue irritation or necrosis at the site ofadministration.

Examples of suitable biocompatible solvents, when used, includeN-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol,acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam,dimethyl-sulfoxide, oleic acid, or 1-dodecylazacycloheptan-2-one. In oneembodiment, solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethyl sulfoxide, and acetone because of their solvating ability andtheir biocompatibility.

The microspheres may be manufactured by incorporating the drug into thepolymer matrix by either dissolving or suspending the drug into polymersolution and the mixture will be subsequently dried by techniquesfamiliar to those skill in the arts to form microspheres. Thesetechniques include but not limited to spray drying, coating, variousemulsion methods and supercritical fluid processing. The microspheresmay be mixed with a pharmaceutically acceptable diluent prior to theadministration for injection. They may also be directly applied to thedesired site, such as a surgical wound or cavity, by various deliverysystems including pouring and spraying. The microspheres may also bemixed with pharmaceutically acceptable ingredients to create ointment orcream for topical applications.

In certain embodiments, the subject polymers are soluble in one or morecommon organic solvents for ease of fabrication and processing. Commonorganic solvents include such solvents as chloroform, dichloromethane,dichloroethane, 2-butanone, butyl acetate, ethyl butyrate, acetone,ethyl acetate, dimethylacetamide, N-methyl pyrrolidone,dimethylformamide, and dimethylsulfoxide.

In addition, the polymer compositions may comprise blends of the polymerwith other biocompatible polymers or copolymers, so long as theadditional polymers or copolymers do not interfere undesirably with thebiocompatible, biodegradable and/or mechanical characteristics of thecomposition. Blends of the polymer with such other polymers may offereven greater flexibility in designing the precise release profiledesired for targeted drug delivery or the precise rate ofbiodegradability desired. Examples of such additional biocompatiblepolymers include other poly(phosphoesters), poly(carbonates),poly(esters), poly(orthoesters), poly(amides), poly(urethanes),poly(imino-carbonates), and poly(anhydrides).

Pharmaceutically acceptable polymeric carriers may also comprise a widerange of additional materials. Without being limited thereto, suchmaterials may include diluents, binders and adhesives, lubricants,disintegrants, colorants, bulking agents, flavorings, sweeteners, andmiscellaneous materials such as buffers and adsorbents, in order toprepare a particular medicated composition, with the condition that noneof these additional materials will interfere with the intended purposeof the subject composition.

Plasticizers and stabilizing agents known in the art may be incorporatedin polymers. In certain embodiments, additives such as plasticizers andstabilizing agents are selected for their biocompatibility.

A composition may further contain one or more adjuvant substances, suchas fillers, thickening agents or the like. In other embodiments,materials that serve as adjuvants may be associated with the polymermatrix. Such additional materials may affect the characteristics of thepolymer matrix that results. For example, fillers, such as bovine serumalbumin (BSA) or mouse serum albumin (MSA), may be associated with thepolymer matrix. In certain embodiments, the amount of filler may rangefrom about 0.1 to about 50% or more by weight of the polymer matrix, orabout 2.5, 5, 10, 25, 40 percent. Incorporation of such fillers mayaffect the biodegradation of the polymeric material and/or the sustainedrelease rate of any encapsulated substance. Other fillers known to thoseof skill in the art, such as carbohydrates, sugars, starches,saccharides, celluoses and polysaccharides, including mannitose andsucrose, may be used in certain embodiments.

In other embodiments, spheronization enhancers facilitate the productionof subject polymeric matrices that are generally spherical in shape.Substances such as zein, microcrystalline cellulose or microcrystallinecellulose co-processed with sodium carboxymethyl cellulose may conferplasticity to the subject compositions as well as implant strength andintegrity. In particular embodiments, during spheronization, extrudatesthat are rigid, but not plastic, result in the formation of dumbbellshaped implants and/or a high proportion of fines, and extrudates thatare plastic, but not rigid, tend to agglomerate and form excessivelylarge implants. In such embodiments, a balance between rigidity andplasticity is desirable. The percent of spheronization enhancer in aformulation depends on the other excipient characteristics and istypically in the range of 10-90% (w/w).

Buffers, acids and bases may be incorporated in the subject compositionsto adjust their pH. Agents to increase the diffusion distance of agentsreleased from the polymer matrix may also be included.

Disintegrants are substances which, in the presence of liquid, promotethe disruption of the subject compositions. Disintegrants are most oftenused in implants, in which the function of the disintegrant is tocounteract or neutralize the effect of any binding materials used in thesubject formulation. In general, the mechanism of disintegrationinvolves moisture absorption and swelling by an insoluble material.Examples of disintegrants include croscarmellose sodium and crospovidonethat, in certain embodiments, may be incorporated into the polymericmatrices in the range of about 1-20% of total matrix weight. In othercases, soluble fillers such as sugars (mannitol and lactose) may also beadded to facilitate disintegration of the subject compositions upon use.

Other materials may be used to advantage to control the desired releaserate of a therapeutic agent for a particular treatment protocol. Forexample, if the sustained release is too slow for a particularapplication, a pore-forming agent may be added to generate additionalpores in the matrix. Any biocompatible water-soluble material may beused as the pore-forming agent. They may be capable of dissolving,diffusing or dispersing out of the formed polymer system whereupon poresand microporous channels are generated in the system. The amount ofpore-forming agent (and size of dispersed particles of such pore-formingagent, if appropriate) within the composition should affect the size andnumber of the pores in the polymer system.

Pore-forming agents include any pharmaceutically acceptable organic orinorganic substance that is substantially miscible in water and bodyfluids and will dissipate from the forming and formed matrix intoaqueous medium or body fluids or water-immiscible substances thatrapidly degrade to water-soluble substances. Suitable pore-formingagents include, for example, sugars such as sucrose and dextrose, saltssuch as sodium chloride and sodium carbonate, and polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol,and polyvinylpyrrolidone. The size and extent of the pores may be variedover a wide range by changing the molecular weight and percentage ofpore-forming agent incorporated into the polymer system.

The charge, lipophilicity or hydrophilicity of any subject polymericmatrix may be modified by attaching in some fashion an appropriatecompound to the surface of the matrix. For example, surfactants may beused to enhance wettability of poorly soluble or hydrophobiccompositions. Examples of suitable surfactants include dextran,polysorbates and sodium lauryl sulfate. In general, surfactants are usedin low concentrations, generally less than about 5%.

Binders are adhesive materials that may be incorporated in polymericformulations to bind and maintain matrix integrity. Binders may be addedas dry powder or as solution. Sugars and natural and synthetic polymersmay act as binders. Materials added specifically as binders aregenerally included in the range of about 0.5%-15% w/w of the matrixformulation. Certain materials, such as microcrystalline cellulose, alsoused as a spheronization enhancer, also have additional bindingproperties.

Various coatings may be applied to modify the properties of thematrices. Three exemplary types of coatings are seal, gloss and entericcoatings. Other types of coatings having various dissolution or erosionproperties may be used to further modify subject matrices behavior, andsuch coatings are readily known to one of ordinary skill in the art.

The seal coat may prevent excess moisture uptake by the matrices duringthe application of aqueous based enteric coatings. The gloss coatgenerally improves the handling of the finished matrices. Water-solublematerials such as hydroxypropyl cellulose may be used to seal coat andgloss coat implants. The seal coat and gloss coat are generally sprayedonto the matrices until an increase in weight between about 0.5% andabout 5%, often about 1% for a seal coat and about 3% for a gloss coat,has been obtained.

Enteric coatings may include polymers which are insoluble in the low pH(less than 3.0) of the stomach, but are soluble in the elevated pH(greater than 4.0) of the small intestine. Polymers such as EUDRAGIT,RohmTech, Inc., Malden, Mass., and AQUATERIC, FMC Corp., Philadelphia,Pa., may be used and are layered as thin membranes onto the implantsfrom aqueous solution or suspension or by a spray drying method. Theenteric coat is generally sprayed to a weight increase of about one toabout 30%, or about 10 to about 15% and may contain coating adjuvantssuch as plasticizers, surfactants, separating agents that reduce thetackiness of the implants during coating, and coating permeabilityadjusters.

The present compositions may additionally contain one or more optionaladditives such as fibrous reinforcement, colorants, perfumes, rubbermodifiers, modifying agents, etc. In practice, each of these optionaladditives should be compatible with the resulting polymer and itsintended use. Examples of suitable fibrous reinforcement include PGAmicrofibrils, collagen microfibrils, cellulosic microfibrils, andolefinic microfibrils. The amount of each of these optional additivesemployed in the composition is an amount necessary to achieve thedesired effect.

The subject polymers may be formed in a variety of shapes. For example,in certain embodiments, subject polymer matrices may be presented in theform of microparticles or nanoparticles. Such particles may be preparedby a variety of methods known in the art, including for example, solventevaporation, spray-drying or double emulsion methods.

The shape of microparticles and nanoparticles may be determined byscanning electron microscopy. Spherically shaped nanoparticles are usedin certain embodiments for circulation through the bloodstream. Ifdesired, the particles may be fabricated using known techniques intoother shapes that are more useful for a specific application.

In addition to intracellular delivery of a therapeutic agent, it alsopossible that particles of the subject compositions, such asmicroparticles or nanoparticles, may undergo endocytosis, therebyobtaining access to the cell. The frequency of such an endocytosisprocess will likely depend on the size of any particle.

In certain embodiments, solid articles useful in defining shape andproviding rigidity and structural strength to the polymeric matrices maybe used. For example, a polymer may be formed on a mesh or other weavefor implantation. A polymer may also be fabricated as a stent or as ashunt, adapted for holding open areas within body tissues or fordraining fluid from one body cavity or body lumen into another. Further,a polymer may be fabricated as a drain or a tube suitable for removingfluid from a post-operative site, and in some embodiments adaptable foruse with closed section drainage systems such as Jackson-Pratt drainsand the like familiar in the art.

The mechanical properties of the polymer may be important for theprocessability of making molded or pressed articles for implantation.For example, the glass transition temperature may vary widely but mustbe sufficiently lower than the temperature of decomposition toaccommodate conventional fabrication techniques, such as compressionmolding, extrusion or injection molding.

In certain embodiments, the polymers and blends, upon contact with bodyfluids, undergo gradual degradation. The life of a biodegradable polymerin vivo depends, among other things, upon its molecular weight,crystallinity, biostability, and the degree of crosslinking. In general,the greater the molecular weight, the higher the degree ofcrystallinity, and the greater the biostability, the slowerbiodegradation will be.

If a subject polymer matrix is formulated with a therapeutic agent,release of such an agent for a sustained or extended period as comparedto the release from an isotonic saline solution generally results. Suchrelease profile may result in prolonged delivery (over, say 1 to about4,000 hours, or alternatively about 4 to about 1500 hours) of effectiveamounts (e.g., about 0.00001 mg/kg/hour to about 10 mg/kg/hour) of theagent associated with the polymer.

A variety of factors may affect the desired rate of hydrolysis ofpolymers, the desired softness and flexibility of the resulting solidmatrix, rate and extent of bioactive material release. Some of suchfactors include: the selection of the various substituent groups, suchas the phosphate group making up the linkage in the polymer backbone (oranalogs thereof), the enantiomeric or diastereomeric purity of themonomeric subunits, homogeneity of subunits found in the polymer, andthe length of the polymer. For instance, the present disclosurecontemplates heteropolymers with varying linkages, and/or the inclusionof other monomeric elements in the polymer, in order to control, forexample, the rate of biodegradation of the matrix.

To illustrate further, a wide range of degradation rates may be obtainedby adjusting the hydrophobicities of the backbones or side chains of thepolymers while still maintaining sufficient biodegradability for the useintended for any such polymer. Such a result may be achieved by varyingthe various functional groups of the polymer. For example, thecombination of a hydrophobic backbone and a hydrophilic linkage producesheterogeneous degradation because cleavage is encouraged whereas waterpenetration is resisted. In another example, it is expected that use ofsubstituent on phosphate in the polymers that is lipophilic, hydrophobicor bulky group would slow the rate of degradation. For example, it isexpected that conversion of the phosphate side chain to a morelipophilic, more hydrophobic or more sterically bulky group would slowdown the rate of biodegradation. Thus, release is usually faster frompolymer compositions with a small aliphatic group side chain than with abulky aromatic side chain.

One protocol generally accepted in the field that may be used todetermine the release rate of any therapeutic agent or other materialloaded in the polymer matrices involves degradation of any such matrixin a 0.1 M PBS solution (pH 7.4) at 37° C., an assay known in the art.For purposes of the present disclosure, the term “PBS protocol” is usedherein to refer to such protocol.

In certain instances, the release rates of different polymer systems maybe compared by subjecting them to such a protocol. In certain instances,it may be necessary to process polymeric systems in the same fashion toallow direct and relatively accurate comparisons of different systems tobe made. Such comparisons may indicate that any one polymeric systemreleases incorporated material at a rate from about 2 or less to about1000 or more times faster than another polymeric system. Alternatively,a comparison may reveal a rate difference of about 3, 5, 7, 10, 25, 50,100, 250, 500 or 750. Even higher rate differences are contemplated bythe present disclosure and release rate protocols.

In certain embodiments, when formulated in a certain manner, the releaserate for polymer systems may present as mono- or bi-phasic. Release ofany material incorporated into the polymer matrix, which is oftenprovided as a microsphere, may be characterized in certain instances byan initial increased release rate, which may release from about 5 toabout 50% or more of any incorporated material, or alternatively about10, 15, 20, 25, 30 or 40%, followed by a release rate of lessermagnitude.

The release rate of any incorporated material may also be characterizedby the amount of such material released per day per mg of polymermatrix. For example, in certain embodiments, the release rate may varyfrom about 1 ng or less of any incorporated material per day per mg ofpolymeric system to about 5000 or more ng/day·mg. Alternatively, therelease rate may be about 10, 25, 50, 75, 100, 125, 150, 175, 200, 250,300, 350, 400, 450, 500, 600, 700, 800 or 900 ng/day·mg. In still otherembodiments, the release rate of any incorporated material may be 10,000ng/day·mg or even higher. In certain instances, materials incorporatedand characterized by such release rate protocols may include therapeuticagents, fillers, and other substances.

In another aspect, the rate of release of any material from any polymermatrix may be presented as the half-life of such material in the suchmatrix.

In addition to the embodiment involving protocols for in vitrodetermination of release rates, in vivo protocols, whereby in certaininstances release rates for polymeric systems may be determined in vivo,are also contemplated by the present disclosure. Other assays useful fordetermining the release of any material from the polymers of the presentsystem are known in the art.

In some embodiments, for delivery of a therapeutic agent, the agent isadded to the polymer composition. A variety of methods are known in theart for encapsulating a biologically active substance in a polymer. Forexample, the agent or substance may be dissolved to form a homogeneoussolution of reasonably constant concentration in the polymercomposition, or it may be dispersed to form a suspension or dispersionwithin the polymer composition at a desired level of “loading” (grams ofbiologically active substance per grams of total composition includingthe biologically active substance, usually expressed as a percentage).

In part, a polymer composition useful in the treatment of pain,inflammation, infection, or other problems, includes both: (a) atherapeutic agent, and (b) a biocompatible and optionally biodegradablepolymer, such as one having the recurring monomeric units shown in oneof the foregoing formulas, or any other biocompatible polymer mentionedabove or known in the art. In certain embodiments in which the subjectcomposition will be used to treat pain, the agent is an analgesic oranesthetic; for inflammation, a steroidal or non-steroidalantiinflammatory agent; and for infection, an antimicrobial effectiveagainst the pathogen(s) of concern, such as an antibiotic, antifungal,antimycotic, antimalarial, antimycobacterial, antiparasitic, orantiviral. In some embodiments, the subject compositions encapsulatemore than one agent for treatment of one or more problems.

In its simplest form, a delivery system for a transmucosal therapeuticagent consists of a dispersion of such an agent into one of the polymersdescribed above. In other embodiments, an article is used forimplantation, injection, or otherwise placed totally or partially withinthe body, the article comprising a therapeutic composition fortransmucosal delivery. It may be particularly important that such anarticle result in minimal tissue irritation when applied to, implantedin or injected into vascularized tissue, hypovascularized tissue,post-operative tissue or tissue exposed to previous radiation that ispart of the nose or nasopharynx. In certain embodiments, a solid,flowable or fluid article is inserted within an anatomic area byimplantation, injection, endoscopy or otherwise being placed within theanatomic area of the subject being treated.

As a structural medical device, the polymer compositions provide a widevariety of physical forms having specific chemical, physical andmechanical properties suitable for insertion into an anatomic area.

Biocompatible delivery systems and articles thereof, may be prepared ina variety of ways known in the art. The subject polymer may be meltprocessed using conventional extrusion or injection molding techniques,or these products may be prepared by dissolving in an appropriatesolvent, followed by formation of the device, and subsequent removal ofthe solvent by evaporation or extraction, e.g., by spray drying. Bythese methods, the polymers may be formed into articles of almost anysize or shape desired, for example, implantable solid discs or wafers orinjectable rods, microspheres, or other microparticles. Typical medicalarticles also include such as implants as laminates for degradablefabric or coatings to be placed on other implant devices.

Nasal devices may be provided with one or more therapeutic agentsincorporated in gels, polymers, powders, and/or liquids that coat, areembedded in or through the device. The structure of the device itselfmay be formed in whole or in part by the drug formulation. The nasaldevice may dissolve in whole or in part with use or may benondissolvable. A device may be inserted temporarily or permanently.

A therapeutic formulation may be selected so that inhalation causesdislodgment or vaporization of a therapeutic into the patient's airsteamfor delivery deeper in the airway (for example, in the brachial treeand/or alveoli).

In one embodiment, certain polymer compositions may be used to form asoft, drug-delivery “depot” that can be administered as a liquid, forexample, by injection, but which remains sufficiently viscous tomaintain the drug within the localized area around the injection site.By using a polymer composition in flowable form, even the need to makean incision can be eliminated. In any event, the flexible or flowabledelivery “depot” will adjust to the shape of the space it occupieswithin the body with a minimum of trauma to surrounding tissues.

When the polymer composition is flexible or flowable, it may be placedanywhere within the body, including into an anatomic area. It may beinserted into the anatomic area either through an open surgical wound,under direct or indirect vision, or through any of the access devicesroutinely used in the art to enter such areas, for example, indwellingor acutely-inserted catheters, needles, drains, superselectiveangiography means and the like. A flowable or fluid polymer may beadapted for mixing with the transudate or exudate found within orexpected to gather within the anatomic area. A flowable or fluid polymermay be instilled in an anatomic area during surgery on organs orstructures therein to decrease the likelihood of recurrent disease whenthere is a high risk for its development. In certain embodiments, apolymer composition may also be incorporated in access devices so that atherapeutic agent is released into the anatomic area within which theaccess device resides. The polymer composition may also be used toproduce coatings for other solid implantable devices for treatment.

Once a system or implant article is in place, it should remain in atleast partial contact with a biological fluid, such as blood, tissuefluid, lymph, or secretions from organ surfaces or mucous membranes, andthe like to allow for sustained release of any encapsulated therapeuticagent, e.g., a therapeutic agent.

These examples of the clinical utility of the disclosed devices andmethods have been provided for illustrative purposes only. Otherexemplary utilizations will be apparent to practitioners of ordinaryskill in the art using no more than routine experimentation.

The various nasal dilators, stents, and other devices may be combinedwith other forms of therapy to provide multi-modality treatments. Forexample, a person with a nasal or upper airway disorder may be treatedby any combination of a nasal device disclosed herein and a course ofantibiotics (by any route of administration), nasal sprays, and/or nasalirrigators. Disorders that may especially amenable to suchmulti-modality treatment include upper airway allergies, congestion,rhinitis, and sinus infections.

The devices disclosed herein may also be used to reduce or eliminatenasal stenosis and/or scarring following nasal surgery such asseptoplasty or rhinoplasty. A device or devices may be positioned in oneor both nostrils following surgery to help hold the nostril in an openedstructure. The device(s) can also prevent contact between surgicalsurface to prevent formation of adhesions or scar tissue. The device(s)may be employed temporarily or permanently. They may be positioned as astep of a surgical procedure or in an out-patient setting. They may beused as a preventive measure before any postsurgical signs or symptomsoccur, or as a remedial measure after an abnormal healing shape,scarring, or adhesions are observed.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered illustrative and notrestrictive, the scope of the invention being dictated by the appendedclaims rather than by the foregoing description, and all changes whichcome within the meaning and range of equivalency of the claims aretherefore intended to be embraced therein.

We claim:
 1. A pair of nasal inserts, each nasal insert comprising awall in the shape of a frustroconical tube, the wall including a firstend defining a first orifice and a second end defining a second orifice,and wherein: the first end has a diameter, diagonal measurement, orcross-sectional area larger than that of the second end; the first endfurther defines at least one break in the wall, so that the first endincompletely encircles the first orifice, the break increasing theflexibility of the first end; the second end completely encircles thesecond orifice; and further comprising: a flexible and resilient couplerelement that connects to the first end of each nasal insert.
 2. Thenasal inserts of claim 1, wherein the wall defines at least onepassageway transverse to a longitudinal axis of the tube.
 3. The nasalinserts of claim 2, wherein the at least one passageway is continuouswith the at least one break in the wall.
 4. The nasal inserts of claim1, further comprising a foot protruding from the first end of the wall.5. The nasal inserts of claim 4, wherein the foot is so flexible as topermit selective positioning of the foot.
 6. The nasal inserts of claim5, wherein the foot comprises an embedded wire.
 7. The nasal inserts ofclaim 1, further comprising a clip.
 8. The nasal inserts of claim 1,wherein an inner surface of the tube defines at least one groove.
 9. Thenasal inserts of claim 1, further comprising a therapeutic agent. 10.The nasal inserts of claim 9, wherein the therapeutic agent isintegrally formed with the device.
 11. The nasal inserts of claim 9,wherein the therapeutic agent is coated on a surface of the device. 12.The nasal inserts of claim 9, wherein the therapeutic agent is providedwith an insert attached to the device.
 13. The nasal inserts of claim12, wherein the insert is removably attached to the device.
 14. Thenasal inserts of claim 1, further comprising a filter so attached to thedevice as to span the tube.
 15. The nasal inserts of claim 14, whereinthe filter is attached to the device by a snap-fit.
 16. The nasalinserts of claim 14, wherein the filter is attached to the device byhook-and-loop fasteners.
 17. A device comprising the device of claim 1attached to a nasal cannula.
 18. A method of preventing postsurgicalcomplications of nasal surgery comprising: inserting the device of claim1 into nostrils of a subject after performing nasal surgery upon thesubject.